tbuckley/cabot-search huggingface dataset:
Detection of bladder cancer relapse after TURBT through urinary tumor DNA analysis: A prospective real-world evidence study.
Authors: Ruiyun Zhang, Jingyu Zang, Haoran Tang, Feng Xie, Yue Zhang, Di Jin, Lei Qian, Tianxiang Zhang, Shidong Jia, Guanglei Zhuang, Haige Chen
Journal: Journal of Clinical Oncology (2023)

e16605 Background: Bladder cancer is a common malignancy and detection of tumor recurrence is important to improve patient outcomes. Transurethral resection of bladder tumor (TURBT) is the standard treatment for early-stage bladder cancer, but the molecular detection of disease relapse remains a challenge. Reliable and non-invasive methods for monitoring the molecular changes in urine are crucial for timely intervention and disease management. Methods: In this study, 108 patients with early-stage bladder cancer who were selected for detection of disease relapse after the 1 st TURBT (median timing 4.8 months after TURBT) were prospectively enrolled. The molecular recurrence in these patients was detected from the urinary tumor DNA (utDNA) using a targeted next-generation sequencing (NGS) assay (PredicineCARE). This assay identifies somatic alterations in utDNA, including single nucleotide variations (SNVs), gene fusions and copy number variations (CNVs), and based on these variations, the tumor fraction was called to identify molecular relapse in the patients. Results: 77 out of 108 (71.3%) patients were found to be tumor positive in utDNA with a tumor fraction ≥ 0.5%. The assay identified 525 SNVs and 32 CNVs in the tumor positive patients. The most frequently mutated genes in the urine samples were TP53 (38%), TERT (32%), KMT2D (28%), ARID1A (19%), FGFR3 (19%), PIK3CA (14%) and ERBB2 (12%). Conclusions: This study demonstrates the feasibility of using urine ctDNA assay to detect molecular recurrence in early-stage bladder cancer patients treated by TURBT. This information can be used to improve patient outcomes by enabling early detection of tumor recurrence and guiding treatment decisions. The findings of this study highlight the promising potential of urine-based NGS assays for cancer detection and disease surveillance.
MOUNTAINEER-03: Phase 3 study of tucatinib, trastuzumab, and modified FOLFOX6 as first line treatment in HER2+ metastatic colorectal cancer.
Authors: Tanios S. Bekaii-Saab, Eric Van Cutsem, Josep Tabernero, Salvatore Siena, Takayuki Yoshino, Yoshiaki Nakamura, Kanwal Pratap Singh Raghav, Andrea Cercek, Volker Heinemann, David E. Adelberg, Jorge Ramos, Shan Yang, Thierry Andre, John H Strickler
Journal: Journal of Clinical Oncology (2023)

TPS3631 Background: The current standard of care (SOC) for the treatment of metastatic colorectal cancer (mCRC) is multi-agent chemotherapy, with or without a VEGF or EGFR inhibitor. Human epidermal growth factor receptor-2 (HER2) is a validated clinical target in breast and gastric cancers. HER2 amplification occurs in 3%–5% of patients with mCRC; the rate of HER2 amplification can increase to approximately 10% in patients with RAS/BRAF wild-type mCRC tumors. Tucatinib (TUC)—a highly selective, HER2-directed tyrosine kinase inhibitor—is approved in multiple regions for HER2-positive (HER2+) metastatic breast cancer, approved in the US for HER2+ metastatic colorectal cancer, and under investigation in gastrointestinal cancers. MOUNTAINEER (NCT03043313) evaluated the safety and efficacy of TUC and trastuzumab (Tras) in patients with treatment-refractory RAS wild-type, HER2+ mCRC. Results from the primary endpoint analysis showed clinically meaningful activity, with a confirmed objective response rate (ORR) per blinded independent central review (BICR) of 38.1% (95% confidence interval [CI] 27.7, 49.3) and median duration of response per BICR of 12.4 months (95% CI 8.5, 20.5). Results also demonstrated TUC + Tras was well tolerated, with a low discontinuation rate (5.8%) and no deaths due to adverse events. MOUNTAINEER-03 will further investigate TUC in combination with modified FOLFOX (mFOLFOX) and Tras in patients with RAS wild-type HER2+ mCRC. Methods: MOUNTAINEER-03 (NCT05253651) is a global, open-label, randomized, phase III study for first-line treatment of HER2+ and RAS wild-type mCRC. Approximately 400 patients will be randomized 1:1 to the TUC experimental arm (TUC [300 mg orally twice daily] + Tras + mFOLFOX) or the SOC arm (mFOLFOX alone or in combination with either bevacizumab or cetuximab). HER2 status is determined centrally with tissue-based HER2 immunohistochemistry and in situ hybridization assays. Eligible patients must not have received prior treatment in the metastatic setting but may have received adjuvant treatment if completed &gt; 6 months prior to enrollment. Patients must be ≥18 years old with an Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS wild-type mCRC. Patients with treated stable central nervous system metastases are eligible. Randomization is stratified by primary tumor location (left-sided vs other) and liver metastases (presence/absence). The primary endpoint is progression-free survival per RECIST v1.1 assessed by BICR. Key secondary endpoints are overall survival and confirmed ORR per RECIST v1.1 assessed by BICR. Enrollment is ongoing in North America, Asia, Australia, and Europe. Clinical trial information: NCT05253651 .
Identifying osteosarcoma signatures in cell free DNA using 5-hydroxymethylcytosine profiling.
Authors: Evan W Neczypor, Kelly Moore, Elizabeth Zeldin, Linda Nie, Masanori Hayashi, Daniel A. Weiser, Mark A. Applebaum
Journal: Journal of Clinical Oncology (2023)

10022 Background: Osteosarcoma is the most common primary bone tumor in children and adolescents. Prognostic biomarkers are limited, and post-treatment surveillance relies heavily on radiologic imaging. Capture and analysis of cell-free DNA (cfDNA) from the bloodstream is an emerging technique that could be used to provide additional prognostic information and track residual disease following treatment. 5-hydroxymethylcytosine (5-hmC) is an epigenetic marker of open chromatin and active gene expression, and tumor specific patterns of global 5-hmC deposition are identifiable in several cancers and vary according to disease burden. We profiled 5-hmC using plasma-derived cfDNA from osteosarcoma patients and healthy children to assess its utility as a biomarker of disease status. Methods: cfDNA was isolated from patients diagnosed with osteosarcoma and well child controls. Nano-hmC-Seal, a technique developed to isolate 5-hmC-modified DNA fragments, was used to generate sequencing libraries of cfDNA. Genomic DNA from osteosarcoma cell lines was serially diluted with healthy donor-derived cfDNA. DESeq2 was used to identify genes with high 5-hmC deposition in osteosarcoma cell line DNA relative to serial dilutions. In patient cfDNA samples, the relative abundance of 5-hmC deposition on these osteosarcoma genes was determined using gene set variation analysis (GSVA). GSVA returns a score ranging from -1 to 1, with positive values indicating a relative abundance of 5-hmC deposition on osteosarcoma genes. Results: The cohort consisted of 33 healthy children and 17 patients with osteosarcoma including 53 serially collected samples from these patients. 139 osteosarcoma genes were identified and used for GSVA analysis. Patients with osteosarcoma had significantly higher GSVA scores than well children (0.26 vs -0.38; p &lt; 0.001). Hierarchal clustering identified two clusters of samples from children with osteosarcoma. Cluster 1 contained samples with scores correlating with osteosarcoma-derived DNA compared to Cluster 2 (0.14 vs -0.18; p &lt; 0.001). Furthermore, Cluster 1 contained 17 of 23 samples from patients with active disease on clinical imaging (sensitivity = 74%, specificity = 57%). High 5-hmC deposition on MYC was readily identified in one sample obtained at diagnosis from the only patient with a MYC amplified tumor. Additional samples from this patient during treatment showed decreasing 5-hmC deposition on MYC, consistent with a treated tumor shedding less DNA into the blood. Additionally, decreased disease burden following surgical resection was identifiable in 5-hmC profiles (presurgical GSVA score 0.22 vs postsurgical -0.08; p = 0.004). Conclusions: Osteosarcoma 5-hmC signatures can identify patients with active disease. Monitoring cfDNA in osteosarcoma using 5-hmC profiling is a promising technique that warrants further investigation with larger patient cohorts.
Identification and evaluation of a reliable, non-invasive diagnostic method using serum microRNA expression to diagnose high-risk colorectal cancer candidates.
Authors: Dominic Chi-Chung Foo, Lui Ng, Wai-Lun Law
Journal: Journal of Clinical Oncology (2023)

e15519 Background: Screening is of paramount importance in early colorectal cancer detection which can significantly reduce its mortality. This study aims to identify a non-invasive diagnostic method using serum microRNA expression to diagnose colorectal cancer patients. Methods: Serum samples were prospectively collected from CRC patients or normal subjects during 2017 to 2021 in Queen Mary Hospital of Hong Kong and divided into 3 study cohorts: Training cohort (n = 129 per group), Validation cohort (n = 200 per group) and Prediction cohort (n = 260). Quantitative PCR was applied to detect the serum level of 20 candidate microRNAs. Multiple linear regression was used to formulate a serum microRNA panel for diagnosing CRC patients. The performance was evaluated by ROC analysis. The cost-effectiveness was investigating by comparing the cost of two CRC diagnostic strategies comprising of (i) colonoscopy alone and (ii) microRNA panel and followed by colonoscopy strategies to microRNA panel tested positive patients. Results: The values of 3 pairs of serum microRNAs, including miR-106b/miR-1246, miR-106b/miR-16 and miR-106b/miR-21 showed statistical significant difference between CRC patients and normal subjects. A serum microRNA panel formulated from these 3 pairs of microRNAs was able to diagnose CRC patients from normal subjects with high accuracy for both training cohort [AUC: 0.9078 (95% CI, 0.9122 To 0.9734; p &lt; 0.0001)] and Validation cohort (AUC: 0.8904), suggesting that this microRNA panel had a consistent performance across different patient cohorts. Our prediction cohort showed that this microRNA panel was able to screen CRC patients with 85.8% sensitivity, 80.95% specificity, 86.9% positive predictive value and 79.4% negative predictive value. Cost-effectiveness analysis revealed that the strategy of combining serum miRNA test and colonoscopy was a more cost-effective approach compared to colonoscopy alone. The average cost saved per patient was around HK$4010. Conclusions: The serum miRNA test was a feasible, promising and cost-effective non-invasive biomarker for diagnosing CRC patients from normal subjects.
Paclitaxel + ramucirumab versus paclitaxel alone in patients with squamous-cell carcinoma of the esophagus, refractory or intolerant to combination therapy with fluoropyrimidine and platinum-based drugs: Final results from the randomized phase 2 IKF-S627/RAMOS trial of the AIO.
Authors: Magdalena Scheck, Thorsten Oliver Goetze, Thomas Jens Ettrich, Harald Schmalenberg, Michael Clemens, Rolf Mahlberg, Steffen Heeg, Stephan Kanzler, Gunnar Hapke, Peter C. Thuss-Patience, Angelika Kestler, Anne Treschl, Gregg Frost, Moritz Schiemer, Sabine Junge, Claudia Pauligk, Salah-Eddin Al-Batran, Sylvie Lorenzen
Journal: Journal of Clinical Oncology (2023)

e16043 Background: Ramucirumab (Ram) in combination with docetaxel is an approved 2nd-line treatment in patients (pts) with squamous cell carcinomas (SCC) of the lung (REVEL study) and with paclitaxel for esophagogastric adenocarcinoma (RAINBOW study). In SCC of the esophagus, nivolumab is currently the only evidence-based 2 nd -line treatment option. This study evaluates the safety and efficacy of the combination of Ram plus paclitaxel. Methods: This prospective, randomized, open-label, multicenter, phase II trial evaluated paclitaxel plus Ram (Ram 8 mg/kg d1 and d15 and paclitaxel 80 mg/m 2 d1, 8, 15) Arm A vs. paclitaxel alone (80 mg/m 2 d1, 8, 15) Arm B, both q4w. Primary endpoint was overall survival rate at 6months (mos) (OS@6), main secondary endpoints were OS, PFS, objective response rate (ORR) and safety. Results: From 3/2019 to 4/2021, 21/186 planned pts were treated within the study protocol (Arm A 11 pts; Arm B 10 pts) in 10 German centers. Due to slow accrual, the study was terminated prematurely. Median age was 63y, 71% were male and 86% had relevant concomitant disease. Pts. received a median of 9 and 10 cycles Arms A and B, respectively. The most common treatment related AEs in Arm A were leucopenia (54.5%), fatigue (27.3%) and peripheral sensory neuropathy (18.2%). Treatment related adverse events (AEs) ≥ grade 3 occurred in 27% in Arm A and 50% in Arm B with neutropenia being most frequent in Arm B (n=3; 30%). Serious adverse events (SAE) occurred in 36% and 50% in Arms A and B respectively. Median follow-up was 9 months (0.7 – 32.4 months). OS@6 in Arm A was 73% for Ram/paclitaxel and 50% for paclitaxel. However, the study design did not allow for statistical comparison of the arms. ORR (CR+PR 18% vs. 20%) and DCR (55% vs. 60%) were in the same range, as well as median PFS (3.8 vs. 3.5 mos) and OS (12.1 vs. 9.2 mos), for Arms A and B, respectively. Conclusions: Ram and Paclitaxel is considered to show an acceptable tolerability and numerically improved OS@6. Due to the small number of pts the current trial must be considered exploratory and more data are needed in this indication. Clinical trial information: NCT03762564 .
The detection of multiple cancer types with an extended set of methylation and protein markers.
Authors: Slava E. Katerov, Harrison L Fleming, Debra E Rugowski, Justin Heilberger, Tyler Duellman, Jillian M Kirby, Nick Kirchner, Brittany Melah, Jacquelyn Hennek, Hatim T. Allawi
Journal: Journal of Clinical Oncology (2023)

3040 Background: Cancer is the 2 nd leading cause of mortality in the US, with an estimated 1.96M new cases expected in 2023. With guideline recommended screening unavailable for most cancers, multicancer early detection (MCED) tests in development may extend the reach of cancer screening. As part of an ongoing program examining multiple biomarker classes in cancer early detection, we examined the feasibility of combining blood DNA methylation and cancer protein markers for the detection of multiple cancer types. Methods: 236 samples from subjects with cancer (13 tumor organ types) were retrospectively collected and gender/age matched with 146 unscreened non-cancer control samples. Plasma and serum were used for cfDNA methylation analysis of 36 differentially methylated regions and 8 cancer-associated protein markers in a randomized, blinded fashion. Methylated DNA markers (MDMs) were assayed using target enrichment long-probe quantitative-amplified signal assays. Protein markers were assayed with commercial kits. Normalized methylation values/protein concentrations were used to develop a logistic regression model for cancer detection. The model was built with 5 random 0.7/0.3 training/validation splits, keeping case/control, cancer types, gender, and age distributions similar to the original data set. Models for MDMs and protein markers were created, and a combined model including both MDMs and protein markers was also evaluated for performance improvement. Results: A reduced subset of MDM and protein markers was identified to have robust detection of several cancer types. At 99% specificity, overall sensitivity for cancer detection was 68% (95% CI: 62%-74%) for MDMs, 43% (37%-50%) for proteins, and 75% (69%-80%) for MDMs and proteins combined. Conclusions: Building on promising results with mutation and protein biomarker analysis (Science 369:6499, 2020) this pilot study demonstrates the potential of combining DNA methylation and protein biomarkers and contributes to a larger scale effort to develop a multi-biomarker class MCED test (Ann Oncol 2022 Vol. 33:S575). [Table: see text]
Circulating tumor DNA (ctDNA) dynamics in response to checkpoint inhibitor immunotherapy in colorectal cancer.
Authors: Kanchi Patell, Matthew Kurian, Benjamin Booker, Michelle Chung, Alexis Bennett, David L Bajor, AMR Mohamed, Amit Mahipal, Sakti Chakrabarti, J. Eva Selfridge
Journal: Journal of Clinical Oncology (2023)

e15540 Background: Circulating tumor DNA (ctDNA) is emerging as a sensitive and specific non-invasive marker of active disease in patients (pts) with colorectal cancer (CRC) and may be used for monitoring response to immunotherapy (IO) in all solid tumors. However, the dynamics of ctDNA changes in response to IO and their correlation to radiographic response has not been well-established. Methods: We searched for all pts in our institution who received IO for a solid tumor diagnosis and who also received quantitative ctDNA testing using Signatera. We retrospectively evaluated radiographic treatment response using RECIST v1.1 and correlated radiographic response to time-matched changes in quantitative ctDNA. Objective response rate (ORR) was defined as the percentage of pts achieving radiographic partial response (PR) plus complete response (CR). Results: We identified 6 pts with advanced CRC who underwent serial ctDNA testing while receiving IO; all patients had loss of mismatch repair protein expressions. Median age was 70 years (range 35-90), and 50% of patients were female. All pts were actively receiving IO at the time of data cutoff. Two pts were receiving ipilimumab plus nivolumab, the other 4 pts were receiving pembrolizumab; 1 pt had only received 1 cycle of IO at time of cutoff, thus did not have on-treatment imaging and was excluded from further analysis. For the response evaluable patients, ORR was 100%, with all pts (5/5) achieving PR after median of 3 cycles (range 1-3 cycles) of treatment. Quantitative ctDNA decreased by 83-100% in all pts analyzed. 1 pt had radiographic (pseudo-)progression at time of first radiographic assessment, however at this timepoint, ctDNA had decreased by 60%; this pt continued on immunotherapy based on clinical benefit including ctDNA data. Subsequent radiographic assessment of this pt confirmed partial response and ctDNA response decreased by total of 95% after a total of 3 cycles of IO. Conclusions: In this small patient population, we show that quantitative ctDNA directly corresponds to radiographic response to IO, and may guide treatment decisions by differentiating pseudoprogression from true progression. Further longitudinal studies will show if ctDNA changes correlate to duration of response, early identification of treatment resistance, and ultimately survival.
Multisystem immune-related adverse events from dual agent immunotherapy use.
Authors: Yuchen Li, Gregory Russell Pond, Elaine McWhirter
Journal: Journal of Clinical Oncology (2023)

2635 Background: Immune-related adverse events (irAEs) are commonly seen in cancer patients who undergo immunotherapy treatment. Increasingly, there has been recognition that multiple different irAEs can occur during or/and after a single course of immunotherapy treatment, known as multisystem irAEs, though much remains unknown. The primary objective of this study was to assess for rate of multisystem irAEs in patients who received dual agent ipilimumab and nivolumab for cancer treatment. Methods: A retrospective cohort review was completed that included all cancer patients seen at Juravinski Cancer Centre who received at least one dose of ipilimumab and nivolumab from January 1, 2018 to May 31, 2022. Patient characteristics, cancer types, and number and types of irAEs were recorded. Multivariate logistic regressions were also completed comparing those who developed multisystem irAEs, single irAE, and no irAE. Results: A total of 123 patients were included in this study. Median age was 59 years old, with 69% male. 72 out of 123 patients (59%) had melanoma, 50/123 (41%) had renal cell carcinoma (RCC), and 1/123 (1%) had breast cancer. At least one irAE was seen in 72% of patients who were treated with ipilimumab and nivolumab, and most irAEs occurred during the combination phase (89% of first irAE, 59% of second irAE, 75% of third irAE, and 50% of fourth irAE). Multisystem irAEs were seen in 40% of the overall cohort. The most common irAE type was dermatitis (22%), followed by colitis (19%), hepatitis (17%), and thyroiditis (15%). 30 out of 89 patients (34%) who experienced irAE(s) required hospital admission for inpatient treatment of irAE(s). Patients who experienced multisystem irAEs had significantly higher rates of response to immunotherapy irAE (p &lt; 0.001) and improved overall survival (OS) than those who experienced single or no irAE. Conclusions: From our single-centre cohort study, there appeared to be a higher than previously quoted number of patients who experienced irAEs after receiving ipilimumab and nivolumab, with majority of them developing multisystem irAEs. Many patients experienced debilitating associated symptoms and hospital admission relating to irAEs. It is important for both the counselling and consent of patients, and for patient education, to discuss the possibility of multiple irAEs prior to dual immunotherapy initiation.
A pilot trial of personalized neoantigen pulsed autologous dendritic cell vaccine as adjuvant treatment in hepatocellular carcinoma.
Authors: Qiuji Wu, Qiu Li, Li Yang, Heng Xu
Journal: Journal of Clinical Oncology (2023)

e14658 Background: The primary means of treating hepatocellular carcinoma (HCC) is radical surgery. However, HCC has a high propensity to recur post-operatively, and no standard adjuvant therapies have been approved. Tumor neoantigens, which are epitopes derived from tumor-specific mutations, may be utilized in personalized vaccines to activate T cell responses. This trial aims to assess the safety and efficacy of personalized neoantigen pulsed autologous dendritic cell vaccine (Neo-DCVac-02) in patients with HCC. Methods: Eligible patients had histologically confirmed high-risk HCC after radical surgery. Upon obtaining the baseline biopsy specimens and PBMCs of appropriate quality for DNA and RNA sequencing, neoantigen prediction, screening, and synthesis were performed. Subsequently, autologous dendritic cells (DCs) were generated and pulsed with neoantigen peptides to produce Neo-DCVac-02.On day 0, patients were treated with cyclophosphamide at a dose of 250 mg/m 2 . The prepared Neo-DCVac-02 vaccine was administered subcutaneously on day 1, followed by GM-CSF administered daily for 5 days. The primary objectives of this study were to evaluate the feasibility and safety/tolerability. Secondary objectives included assessment of immune responses (via vaccine response: IFNγ ELISpot), recurrence-free survival (RFS), and overall survival (OS). Results: A total of 32 patients provided informed consent to initiate the process of personalized neoantigen discovery, of which 26 (81%) met the requirements for successful product selection for clinical manufacturing. And feasibility was shown with 13 patients receiving Neo-DCVac-02. Thirteen patients did not receive neoantigen vaccines (7 for progressive disease,6 for withdrawal of informed consent because of COVID-19). Treatment was well-tolerated with no grade 2+ treatment-related adverse events (TRAEs). The common grade 1TRAEs were neutropenia (8.3%), injection site reactions (75%), rash (16.7%), fatigue (8.3%), and headache (8.3%). The median follow-up to date is 19.30 (14.4-31.9) months, with median RFS and OS not yet reached and a 1-year RFS of 83%. Five of 13 evaluable patients showed elevated antigen-specific T-cell activity by IFNγ ELISpot for more than 50% of neoantigen peptides in Neo-DCVac-02, and persistent cellular responses were noted out to 1 year. Increases in activation/co-stimulatory of T cells seen after treatment with Neo-DCVac-02 revealed by Flow-cytometric analyses, suggest immune priming. Conclusions: These data demonstrate that Neo-DCVac-02 is safe, well tolerated, and able to generate durable antigen-specific lymphocyte immune responses. Early signs of clinical efficacy were observed in HCC patients. Clinical trial information: NCT04147078 .